Functional and Anatomical Outcomes of Faricimab in Previously Treated Wet Age-Related Macular Degeneration: Systematic Review and Pooled Analysis

Abstract

Introduction

To evaluate the outcomes of intravitreal faricimab (IVF; Vabysmo^®) in previously treated patients with wet age-related macular degeneration (wAMD), focusing on best available visual acuity (BAVA), central subfield thickness (CST), injection interval, complications, fluid resolution, and reversion rates to prior therapies.

Methods

The PubMed, Embase, and Google Scholar databases were searched for studies reporting outcomes of treatments for previously treated cases of wAMD. Mean differences (MD) with 95% confidence intervals (CI) were used to compute the effect size of the change in outcomes.

Results

A total of 29 studies with 2070 patients (1003 women, mean age 78.9 years) and 2128 eyes were included. BAVA and CST were reported in 28 studies, fluid status in 21, injection interval in 14, and reversion rates in 6. Pooled analysis showed significant but modest improvement in BAVA when IVF was given for > 6 months (MD = −0.026 LogMAR, p < 0.05) but not at earlier follow-ups. A similar trend was noted with injection interval extension when IVF was given beyond 6 months (MD = +2.1 weeks, p < 0.05). CST reduction was observed at all time points (overall MD = −37.7 μm, p < 0.05). Complication rates were reported in nine studies, with an overall rate of 1.2%, including retinal pigment epithelium tear, intraocular inflammation, endophthalmitis, and subretinal hemorrhage. Reversion to prior or other anti-vascular endothelial growth factor (anti-VEGF) therapy was reported in six studies, occurring in 23% of eyes.

Conclusions

We reported the outcomes of utilizing IVF in previously treated cases of wAMD. IVF showed a significant improvement in CST at all time points and in the extension of injection interval. Visual outcomes remained unchanged when followed for less than 6 months but improved significantly but modestly when followed for more than 6 months. Switching to intravitreal faricimab may be a useful treatment option for previously treated patients with wAMD, with a goal of reducing treatment burden and improving treatment efficacy.

Key Summary Points

This research aims to consolidate the findings from the real-world studies about using intravitreal faricimab (IVF) in patients with wet age-related macular degeneration (wAMD).

Intravitreal faricimab demonstrated a significant reduction in central subfield thickness (CST) as early as 1 month, with sustained improvement observed for up to 1 year. Studies with follow-up beyond 6 months also reported extended injection intervals. Best available visual acuity (BAVA) improved statistically significantly after more than 6 months of follow-up, although the change was not clinically meaningful.

IVF demonstrated improved anatomical outcomes compared with aflibercept and brolucizumab; however, there were no significant differences in functional outcomes.

The overall complication rate was 1.2%, and 23% of patients reverted to other anti-vascular endothelial growth factor (anti-VEGF) therapies.

Switching to IVF may be a useful treatment option for previously treated patients with wAMD.

Introduction

Age-related macular degeneration (AMD) is one of the leading causes of blindness in the USA, affecting more than 11 million American adults, and is the third leading cause of blindness globally. Wet AMD (wAMD) represents 10–15% of AMD cases but accounts for a disproportionate rate of severe vision loss compared with dry AMD [1, 2].

Multiple proangiogenic factors have been implicated in the pathogenesis of wAMD, with current pharmacological agents primarily targeting vascular endothelial growth factor (VEGF) [3]. The advent of anti-VEGF intravitreal injections, such as bevacizumab, ranibizumab, and aflibercept, changed the paradigm of treating wAMD. Despite the effectiveness of anti-VEGF inhibitors, there is a subset of eyes refractory to or with suboptimal responses to treatment despite frequent intravitreal injections. For these cases, physicians may opt to administer anti-VEGF medications more frequently or at higher doses [4].

Faricimab (Vabysmo) is a monoclonal antibody with a unique bispecific modality that inhibits both VEGF and angiopoietin 2 (Ang2) activity simultaneously. In its physiological state, Ang2 inhibits phosphorylation of tyrosine kinase receptors, hypothetically making the endothelium more responsive to VEGF. In wAMD, Ang2 is upregulated, further sensitizing the endothelium to VEGF, thus promoting fluid leakage [5]. The inhibition of Ang2 upregulation is purported to stabilize the endothelium and prolong the treatment effect of anti-VEGF therapy [6, 7–8]. The phase 3 clinical trials that evaluated intravitreal faricimab (IVF) for wAMD, TENAYA and LUCERNE, have demonstrated a more durable treatment response, greater drying effect, and non-inferior efficacy compared with aflibercept [9, 10–11]. Faricimab was approved by the US Food and Drug Administration (FDA) in January 2022 for the treatment of both neovascular age-related macular degeneration and diabetic macular edema. This regulatory approval marked a significant milestone and has likely influenced real-world treatment adoption and switching strategies, as clinicians began integrating faricimab into clinical practice shortly thereafter. However, these clinical trials included only treatment-naïve patients, the results of which might not be generalizable to the real world of previously treated eyes with wAMD switched to intravitreal faricimab (IVF). Since the pivotal clinical trials, multiple IVF studies have been published specifically evaluating outcomes in previously treated patients with wAMD.

The purpose of this study is to perform a systematic review and meta-analysis to assess the functional and anatomical outcomes, through best available visual acuity (BAVA), central subfield thickness (CST), and injection interval measurements, of IVF when used in previously treated patients with wAMD.

Methods

Search Strategy

A systematic literature search of PubMed, Embase, and Google Scholar was performed to identify studies published on faricimab in previously treated wAMD, filtered to only studies in English. An example of the search strategy utilized in PubMed can be found in Appendix 1. The end date of the search period was 1 September 2024. The meta-analysis was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [12] and the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines [13], which can be found in the Supplementary Material. Two independent reviewers (A.K. and M.E.Q.G.) assessed the titles and abstracts. Disagreements in selection were resolved by discussion or with a third independent reviewer (R.E.R.L.). The full text of the selected papers was then screened by A.K. and M.E.Q.G. The protocol for this review was registered at the International Prospective Register of Systematic Reviews (PROSPERO) in July 2024; the code for this protocol is CRD42024568869. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Inclusion and Exclusion Criteria

We included peer-reviewed observational studies that assessed IVF in patients with wAMD who had been previously treated with at least one other anti-VEGF agent. Studies were eligible if they administered more than one IVF injection and reported at least one of the following outcomes: best available visual acuity (BAVA), central subfield thickness (CST) on optical coherence tomography (OCT), injection interval, incidence of adverse events or complications, percentage of dry retinas (defined as complete resolution of intraretinal or subretinal fluid), or failure of IVF (defined as persistent, worsening, or recurrent fluid). Animal studies, review articles, conference abstracts, and case reports were excluded.

This selection strategy was guided by our aim to evaluate real-world treatment patterns and outcomes in non-treatment-naïve, clinically relevant populations. We prioritized studies that assessed outcomes before and after initiating IVF, as well as those comparing IVF with other anti-VEGF agents, to better understand switching strategies in suboptimal responders.

Two reviewers (A.K. and M.E.Q.G.) independently extracted the following data from each included study: first author; publication date; study design; sample size; inclusion and exclusion criteria; length of follow-up; mean and standard deviation (SD) of BAVA; CST; injection interval; proportion of dry macula before starting faricimab and at the last visit; complications; reversion rate to previous anti-VEGF; mean AMD history; and mean previous number of anti-VEGF injections. BAVA was converted to LogMAR when reported in Snellen or Early Treatment Diabetic Retinopathy Study (ETDRS).

Studies were excluded if one of the following conditions was met: outcomes of interest were not reported, inability to calculate or contact the authors for the necessary data, or studies reporting faricimab outcomes for treatment-naïve patients.

Quality Assessment and Data Analysis

To evaluate and synthesize the evidence from included studies, we employed two established frameworks: the Risk of Bias in Non-Randomized Studies-of Interventions (ROBINS-I) [14] tool for assessing risk of bias and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) [15] approach for creating a summary of findings and assessing evidence quality using GRADEpro GDT software [16].

R version 4.3.2 and RStudio [17] were used to perform the meta-analysis using the “meta” library [18]. Mean differences (MD) with 95% confidence intervals (CI) were used to calculate the effect size of the continuous variables (BAVA, CST, and injection interval). Means for each group, before and after the intervention, were collected, and if not reported, the first or corresponding author was contacted to provide the data. Meta-analysis for proportions using DerSimonian Laird method was used for binary variables (proportion of dry macula before and after faricimab). P-value < 0.05 was considered statistically significant. Heterogeneity between studies was assessed using chi-squared Q test and I² statistics. Random effects model was used because it assumes that effect sizes are sampled from a universe of effect sizes due to the heterogeneity of populations studied, protocols used, and follow-up length.

Demographic data were reported as percentages or weighted means and SD. Publication bias was assessed using funnel plots. Studies were stratified on the basis of the reported follow-up duration: 1 month, between 1 and 6 months, and more than 6 months. Observational studies were included in the main analysis of outcomes before and after IVF, as well as separately, comparing IVF with other anti-VEGFs. A sensitivity analysis was carried out by distinguishing studies that included treatment-resistant patients, defined as persistent, recurrent, or worsening fluid after three injections and assessing the outcomes of IVF.

Outcome Measures

The primary outcomes of interest in this review were BAVA, CST, and injection intervals before and after initiating IVF treatment. Key time points for assessment included 1 month, 1–6 months, and 12 months of follow-up post IVF. Secondary outcomes included reversion rates, treatment-related complications, and the proportion of eyes achieving a dry macula before and after IVF.

Results

Search Strategy

The flow diagram of the search strategy results is shown in Fig. 1. Two researchers (A.K. and M.E.Q.G.) screened the titles and abstracts of a total of 966 studies from the three databases. A total of 834 were excluded for being irrelevant (n = 726), reviews (n = 80), case reports (n = 15), animal models (n = 8), or infographics (n = 5). This yielded 132 potentially relevant studies. After removing the duplicates, this number decreased to 51, out of which 29 reported faricimab outcomes for previously treated patients with wAMD and were included in the final analysis.

[See PDF for image]

Fig. 1

PRISMA 2020 flow diagram for new systematic reviews that included searches of databases and registers only. RCT randomized control trial, wAMD wet age-related macular degeneration

Study Characteristics

In total, 29 studies [11, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44–45] published between 2019 and 2024 met the inclusion criteria and were included in this meta-analysis. Study characteristics are presented in Tables 1 and 2. Five of 29 studies were observational studies [11, 21, 39, 45, 46] utilizing control groups. Two of these studies compared IVF outcomes in previously treated versus treatment-naïve patients [11, 39]; one compared IVF with intravitreal aflibercept (IVA) [46]; and two compared IVF to intravitreal brolucizumab (IVBr) in previously treated patients [21, 45]. These studies were included in the main analysis, comparing outcomes before and after IVF, and as a separate subgroup analysis comparing IVF with other anti-VEGFs. Further, 24/29 studies [19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37–38, 40, 41, 42, 43–44] were classified as time-interrupted studies, where the same patient was used as their own control. Follow-up time stratification included 1 month (13 studies reported CST and 12 reported BAVA), between 1 and 6 months (8 studies reported BAVA and CST; 3 reported injection interval), and more than 6 months (14 reported BAVA, 13 CST, and 11 injection interval). For studies reporting results at multiple time points, each result was categorized and included in the corresponding time-point analysis.

Table 1. Characteristics of included observational studies

Authors	Year	Intervention group	Comparison group	Total eyes	Number of eyes faricimab group	Number of eyes comparison group	Mean follow-up time (weeks)	Mean previous injections	Mean disease history (months)	Primary outcome(s)
Khanani et al.	2023	Previously treated started on IVF	Treatment naïve started on IVF	376	337	39	NAa	NA	NA	BAVA–CST
		Previously treated received three IVF injections	Treatment naïve received three IVF injections	88	75	13	26	NA	NA	BAVA–CST
Kin et al.	2024	Previously treated started on IVF	Previously treated started on IVBr	35	15	20	12	5.87 (IVF group) 7.35 (IVBr group)	NA	BAVA–CST
Matsubara et al.	2023	Previously treated started on IVF	Previously treated started on IVBr	27	13	14	4	35.5b (IVF group) 22.5b (IVBr group)	NA	BAVA–CST
Rush et al.	2023	Previously treated started on IVF	Previously treated started on IVA	55	28	27	17.4	16.8 (IVF group) 17.7 (IVA group)	NA	BAVA–CST
Stanga et al.	2023	Previously treated started on IVF	Treatment naïve started on IVF	11	8	3	4	8b	NA	BAVA–CST

AMD age-related macular degeneration, BAVA best available visual acuity, CST central subfield thickness, IVA intravitreal aflibercept, IVBr intravitreal brolucizumab, IVF intravitreal faricimab

^aThese patients received only one injection; the subgroup below (italicized), from the same study, was followed for 26 weeks

^bThe reported value is median, not mean

Table 2. Characteristics of included interrupted time series studies

Authors	Year	Intervention	Previous anti-VEGF	Number of eyes	Mean follow-up time (weeks)	Mean previous injections	Mean disease history (months) ± SD	Primary outcome(s)
Aljundi et al.	2024	IVF	IVA–IVB–IVBr–IVR	44	16	32	NA	BAVA–CST
Aljundi et al.	2024	IVF	IVA–IVB–IVBr–IVR	33	52	44	NA	BAVA–CST
Cheng et al.	2023	IVF	IVA–IVB–IVR	13	14.7	NA	49.9 ± 25.3	BAVA–CST
Eckardt et al.	2024	IVF	IVA–IVR	58	12	37.5	NA	BAVA–CST–injection interval
Goodchild et al.	2024	IVF	IVA	98	26	28	44 ± 34	BAVA–CST–injection interval
Grimaldi et al.	2023	IVF	IVA–IVR	26	30.2	NA	NA	BAVA–CST–injection interval
Hikichi et al.	2023	IVF	IVA–IVR	48	26	38.7	64.9 ± 6.0	BAVA–CST–injection interval
Inoda et al.	2023	IVF	IVA–IVBr	80	4	22.4	71.0 ± 46.9	BAVA–CST
Kataoka et al.	2024	IVF	IVA	53	26	43.5	NA	BAVA–CST–injection interval
Kenworthy et al.	2023	IVF	IVA–IVBr–IVR	31	26	41.4a	NA	BAVA–CST–injection interval
Khodor et al.	2024	IVF	IVA–IVB–IVR	135	50.4	32.3	NA	BAVA–CST–injection interval
Kishi et al.	2023	IVF	IVA	55	16	23.7	55.4 ± 44.9	BAVA–CST–injection interval
Leung et al.	2023	IVF	IVA–IVR	190	35	34.2	42 ± 29.5	BAVA–CST–injection interval
Machida et al.	2024	IVF	IVA	43	26	38	NA	BAVA–CST–injection interval
Muth et al.	2024	IVF	IVA–IVB–IVR	57	4	33a	NA	BAVA–CST
Ng et al.	2024	IVF	IVA–IVBr–IVR	63	30.3	41.5	65.4 ± 39.0	BAVA–CST–injection interval
Pandit et al.	2023	IVF	IVA–IVB–IVR	218	22.8	34.2	52 (range: 19–85)	BAVA–CST
Raimondi et al.	2023	IVF	IVA	81	5	29.5	NA	BAVA–CST
Rush et al.	2023	IVF	IVA	54	52	17.3	NA	BAVA–CST
Schneider et al.	2024	IVF	IVA	50	4	33a	NA	BAVA–CST–injection interval
Sim et al.	2024	IVF	IVA–IVR	106	52	33.4	51.3 ± 34.9	BAVA–CST–injection interval
Szigiato et al.	2023	IVF	IVA–IVB–IVBr–IVR	126	24.3	NA	NA	BAVA–CST–injection interval
Takahashi et al.	2024	IVF	IVBr	40	52	26a	NA	BCV–CST–injection interval
Tamiya et al.	2023	IVF	IVA	25	8.7	25.3	72 ± 63.5	BAVAb–CSTb–retinal fluid

AMD age-related macular degeneration, BAVA best available visual acuity, CST central subfield thickness, IVA intravitreal aflibercept, IVB intravitreal bevacizumab, IVBr intravitreal brolucizumab, IVF intravitreal faricimab, IVR ontravitreal ranibizumab

^aThe reported value is median, not mean

^bMissing data that could not be retrieved

Quality Assessment of Included Studies

No randomized clinical trials (RCT) were included, as all RCTs performed to date recruited treatment-naïve patients. All studies included were retrospective, and assignment of IVF was based on the discretion of the treating physician. GRADE was used to assess certainty of evidence for all three primary outcomes, BAVA, CST and injection interval. Risk of bias was graded as “very serious,” inconsistency “serious,” publication bias “strongly suspected,” and plausible confounding “would reduce demonstrated effect,” for all the variables, while large effect was “large” for BAVA and injection interval and “very large” for CST. The summary of findings and certainty of evidence is found in Table 3.

Table 3. Summary of findings: faricimab compared with previous anti-VEGF for patients with wAMD

Population: patients with wAMD; intervention: faricimab; comparison: previous anti-VEGF
Outcomes	Mean (95% CI) with previous anti-VEGF	MD (95% CI) after faricimab	No. of eyes (no. of studies)	Certainty of the evidence (GRADE)	Comments
BAVA (LogMAR) Scale from –2.7 to 2.7 1 month of follow-up	0.488 (0.486–0.490)	0.0001 (−0.003–0.003)	1131 (12)	⨁⨁◯◯ Lowa	Faricimab likely results in little to no difference in BAVA between 1 and 6 months
BAVA (LogMAR) Scale from −2.7 to 2.7 1–6 months of follow-up	0.52 (0.49–0.54)	−0.023 (−0.1–0.058)	557 (8)	⨁⨁◯◯ Lowa	Faricimab likely results in little to no difference in BAVA after 1 month
BAVA (LogMAR) Scale from −2.7 to +2.7 6–12 months of follow-up	0.53 (0.52–0.54)	−0.045 (−0.076 to −0.013)	1006 (14)	⨁⨁◯◯ Lowa	Faricimab likely improves best corrected vision slightly beyond 6 months
CST (μm) 1 month of follow-up	327.3 (326.6–328.0)	−22.6 (−29 to −16)	1144 (13)	⨁⨁⨁◯ Moderatea,b	Faricimab results in large reduction in CST at 1 month
CST (μm) 1–6 months of follow-up	330.5 (323.3–337.8)	−40.8 (−58 to −23)	557 (8)	⨁⨁⨁◯ Moderatea,b	Faricimab likely results in a large reduction in CST between 1 and 6 months
CST (μm) 6–12 months of follow-up	366 (364–368)	−44.5 (−60 to −28)	1006 (14)	⨁⨁⨁◯ Moderatea,b	Faricimab results in a reduction in CST after 6 months of treatment
Injection interval (weeks) 1–6 months of follow-up	5.4 (5.2–5.6)	+0.56 (−0.70–1.87)	239 (3)	⨁⨁◯◯ Lowa	Faricimab may result in little to no difference in injection interval between 1 and 6 months of treatment
Injection interval (weeks) 6–12 months of follow-up	4.79 (4.75–4.83)	+2.1 (1.3–2.9)	844 (11)	⨁⨁◯◯ Lowa,b	Faricimab may increase injection interval after 6 months of treatment

GRADE Working Group grades of evidence: high certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect

BAVA best available visual acuity, CI confidence interval, CST central subfield thickness, LogMAR logarithm of the minimum angle of resolution, MD mean difference, VEGF vascular endothelial growth factor

Demographic Outcomes

A total of 2128 eyes of 2070 patients, 1003 (48.4%) women, mean age of 78.9 ± 2.2 years, of which 423 (18.7%) eyes were Asian, and a mean follow-up time of 22.4 ± 15.3 weeks were collected. The mean number of previous injections, reported in 17 studies, was 32.7 ± 7.6 injections, with a mean wAMD disease history of 57.2 months.

BAVA Outcome

The BAVA MD for the 12 studies with 1-month follow-up [11, 20, 22, 25, 26, 27, 28–29, 37, 39, 43, 45] was 0.0001 LogMAR [95% CI (−0.003–0.003), p > 0.05, I² = 0%]. For the eight studies with follow-up between 1 and 6 months [21, 22, 24, 29, 31, 37, 38, 46], the MD was −0.023 LogMAR [95% CI (−0.1–0.058), p > 0.05, I² = 70%]. However, for the 14 studies with follow-up exceeding 6 months [11, 19, 23, 25, 28, 30, 32, 33, 34, 35–36, 40, 41–42] the MD was −0.045 LogMAR [95% CI (−0.076; −0.013), p < 0.05, I² = 79%], indicating statistically significant but clinically modest improvement. Forest plots stratified by follow-up durations are shown in Fig. 2a, b, and c.

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Fig. 2

a Forest plot showing change in BAVA in the studies with 1 month of follow-up. b Forest plot showing change in BAVA in studies with 1–6 months of follow-up. c Forest plot showing change in BAVA in studies with more than 6 months of follow-up. BAVA best available visual acuity, CI confidence interval, IVF intravitreal faricimab, MD mean difference, SD standard deviation

In the subgroup analysis of observational studies, one study [46] compared IVF with IVA in previously treated patients over a 4-month follow-up period. While the MD favored IVF [−0.08 LogMAR, 95% CI (−0.02–0.18)], the result was not statistically significant (p > 0.05). In addition, two studies [21, 45] comparing IVF with IVBr in previously treated patients reported no significant difference in BAVA compared with baseline, with an MD of −0.025 LogMAR (p > 0.05).

CST Outcome

The CST MD for the 13 studies with 1 month of follow-up [11, 20, 22, 25, 26, 27, 28–29, 37, 38–39, 43, 45] was −22.6 μm [95% CI (−29 to −16), p < 0.05, I² = 0%]; for the 8 studies with follow-up between 1 and 6 months [21, 22, 24, 29, 31, 37, 38, 46], it was −40.8 μm [95% CI (−58 to −23), p < 0.05, I² = 62%], and for the 14 studies with more than 6 months of follow-up [11, 19, 23, 25, 28, 30, 32, 33, 34, 35–36, 40, 41–42], it was −44.5 μm [95% CI (−60 to −28), p < 0.05, I² = 95%]. The MD of CST was statistically significant at all time points. Forest plots of the studies stratified on the basis of follow-up times are shown in Fig. 3a–c, respectively.

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Fig. 3

a Forest plot showing change in CST in studies with 1 month of follow-up. b Forest plot showing change in CST in studies with 1–6 months of follow-up. c Forest plot showing change in CST in studies with more than 6 months of follow-up. CI confidence interval, CST central subfield thickness, IVF intravitreal faricimab, MD mean difference, SD standard deviation

In the subgroup analysis of observational studies, one study [46] compared IVF with IVA and reported that IVF led to a significantly greater reduction in CST [MD: −44.1 μm, 95% CI (−68.1 to −20.1), p < 0.05]. Similarly, two studies [21, 45] comparing IVF with IVBr found that IVF resulted in a more substantial CST reduction (MD: −78.5 μm, p < 0.05).

Injection Interval

Injection interval was not reported in the studies with 1 month of follow-up, and, therefore, no comparative analysis was able to be performed. In the three studies [24, 31, 37] with follow-up between 1 and 6 months, the injection interval demonstrated an improvement of +0.56 weeks [95% CI (−0.7–1.87), p > 0.05, I² = 93%]. In the 11 studies [19, 23, 25, 28, 30, 32, 34, 35–36, 41, 42] with more than 6 months of follow-up, there was a statistically significant prolongation in injection frequency of +2.1 weeks [95% CI (1.3–2.9), p < 0.05, I² = 97%]. Forest plots of the studies stratified based on follow-up times are shown in Fig. 4a and b, respectively.

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Fig. 4

a Forest plot showing change in injection interval in studies with 1–6 months of follow-up. b Forest plot showing change in injection interval in studies with more than 6 months of follow-up. CI confidence interval, IVF intravitreal faricimab, MD mean difference SD standard deviation

Retinal Fluid Outcome

In total, 21 studies [11, 20, 22, 23, 24, 25, 26, 27, 28–29, 31, 33, 34, 35, 36–37, 39, 41, 42, 44, 45] reported the fluid status of the macula before and after receiving IVF. Only 9% (n = 175/1902) of the patients in these studies had no fluid present prior to IVF switch. The overall percentage of dry macula after treatment was 41% [95% CI (32–51%), I² = 98.6%]. When stratified on the basis of follow-up time, studies with 1 month of follow-up had a proportion of eyes without fluid of 47% [95% CI (42–51%), I² = 0%]; those with 1–6 months of follow-up had a proportion of 40% [95% CI (31–49%), I² = 75%]; while the studies with more than 6 months of follow-up had a dry proportion of 42% [95% CI (26–58%), I² = 98.9%].

Most studies distinguished between intraretinal fluid (IRF) and subretinal fluid (SRF). When stratifying by type of fluid present (IRF versus SRF), 21 studies reported IRF outcomes, and 13 [11, 20, 22, 25, 27, 29, 31, 33, 34, 37, 42, 44, 45] studies reported SRF outcomes. In total, 47% (n = 902/1902) of all patients had IRF, and 42% (802/1902) had SRF. Stratifying IRF outcomes by time, the proportion of dried macula at 1 month [11, 20, 27, 45] was 30% [95% CI (16–43%), I² = 67%]; between 1 and 6 months [22, 24, 29, 31, 37, 44] it was 20% [95% CI (10–30%), I² = 67.8%]; and those with more than 6 months [11, 23, 25, 33, 34, 35–36, 41, 42] of follow-up had a dry proportion of 38% [95% CI (21–56%), I² = 98.2%] out of the initial 902 patients with IRF. As for SRF proportion of dried macula at 1 month [11, 20, 27, 45], it was 61% (95% CI [55–67%], I² = 0%), between 1 and 6 months [22, 29, 31, 37, 44] it was 42% [95% CI (30–53%), I² = 76.6%], and those with more than 6 months [11, 25, 33, 34, 42] of follow-up had a dry proportion of 44% [95% CI (17–73%), I² = 97.8%] out of the initial 802 patients with SRF.

Treatment-Resistant Subgroup

A total of 16 studies [19, 24, 25, 26, 27, 28–29, 32, 33–34, 36, 37–38, 40, 41, 46] reported IVF outcomes in patients with treatment-resistant AMD, defined as persistent, recurrent, or worsening fluid after three anti-VEGF injections. Six papers [26, 27, 29, 37, 38, 46] followed patients between 1 and 6 months; the BAVA MD was −0.049 LogMARs (95% CI [−0.12–0.023], p > 0.05, I² = 58.3%) and the CST MD was −47.4um (95% CI [−62.4; −32.4], p < 0.05, I² = 15.3%). There were insufficient data to analyze the injection interval. Ten papers [19, 24, 25, 28, 32, 33–34, 36, 40, 41] followed patients for more than 6 months; the BAVA MD was −0.018 [95% CI (−0.07–0.03), p > 0.05, I² = 87.9%], the CST MD was −40.4 μm [95% CI (−52.9 to −27.9), p < 0.05, I² = 58.8%], and the injection interval extension was +2.1 weeks [95% CI (1.0114–3.1940), p < 0.05, I² = 96.8%].

Reversion and Complication Rates

Nine studies [11, 22, 25, 28, 31, 35, 36–37, 41] reported complications in 1.2% of the eyes (23 out of 1794), the most frequent being retinal pigmented epithelial (RPE) tear (n = 8, 0.5%), followed by intraocular inflammation (n = 5, 0.3%), endophthalmitis (n = 3, 0.16%), subretinal hemorrhage (n = 3, 0.16%), corneal abrasion/ulcer (n = 2, 0.1%), stroke (n = 1, 0.05%), and headache (n = 1, 0.05%). Of note, some of these patients that experienced complications continued to receive faricimab, while others reverted back to their previous anti-VEGF therapy.

Six studies [25, 28, 30, 31–32, 41] reported the patients who reverted to their prior anti-VEGF therapy after trialing IVF. A total of 23% of the eyes (153 out of 664) were reverted. Reasons for reverting from IVF back to previous or other anti-VEGF were as follows: worsening fluid in 61.4% (94 eyes), no improvement compared with previous anti-VEGF in 32% (49 eyes), development of adverse events in 3.9% (6 eyes), lost to follow-up in 1.3% (2 eyes), coronavirus disease (COVID) infection in 0.7% (one patient), and based on patient’s decision to discontinue all treatment in 0.7% (one patient).

Discussion

To our knowledge, this is the first study to systematically review and meta-analyze the outcomes of IVF in previously treated patients with wAMD. IVF significantly but modestly improved BAVA for patients with wAMD followed for more than 6 months after switching from other anti-VEGF agents; there was no significant BAVA change in patients followed for less than 6 months. In addition, there were statistically significant anatomical improvements in CST at all time points after switching to IVF, and a statistically significant increase in injection interval by 2 weeks on average. These findings suggest a delayed improvement in BAVA (beyond 6 months) compared with a more rapid effect on fluid reduction, possibly owing to a gradual effect of Ang-2 inhibition on vascular remodeling [47, 48] or to a gradual restoration in retinal function once a reduction in macular fluid was achieved. The magnitude of visual gain was low (−0.07 LogMARs), likely because the greatest visual gain already occurred at the initiation of anti-VEGF treatment at diagnosis of wAMD. This is dissimilar to the conclusion reached by the phase 3 wAMD RCTs (TENAYA/LUCRENE) that recruited treatment-naïve patients, where the improvement in BAVA was rapid (as early as 2 months), pronounced, and sustained for 2 years [9, 49, 50]. As for CST, TENAYA/LUCRENE found a rapid and significant decrease following initiation of IVF in treatment-naïve patients, which persisted up to 2 years. In our study, a rapid and significant decrease in CST after initiation of IVF was also seen in previously treated patients, starting as early as 1 month and remaining as long as 6 months post IVF. In regard to extending the injection interval, although no patients achieved an injection interval of 16 weeks as reported in the phase 3 studies [9], there was a statistically significant increase in injection interval by 2.2 weeks (95% CI [1.06–3.35]), which may be meaningful for this more difficult-to-treat cohort. The differences observed between our results and those from the RCTs are likely due to variations in inclusion criteria and patient populations. While the IVF RCTs exclusively enrolled treatment-naïve patients [9], the studies we analyzed included previously treated, real-world patients and employed different criteria for switching to IVF.

Comparing IVF with other anti-VEGFs, our results showed that in previously treated patients with wAMD, the functional outcomes were comparable between IVF and IVBr and IVA, while anatomically, IVF had better outcomes compared with IVA and IVBr (compared with IVA: CST MD: −44.1 μm, compared with IVBr: MD: −78.5 μm, both p < 0.05). Phase 3 trials have demonstrated that faricimab offers extended durability with comparable efficacy and anatomical outcomes to aflibercept. The TENAYA and LUCERNE studies reported that nearly 80% of patients achieved 12- or 16-week dosing intervals while maintaining non-inferior visual outcomes compared with aflibercept [9, 49]. The HAWK and HARRIER trials evaluating brolucizumab also showed extended durability, but concerns regarding intraocular inflammation and retinal vasculitis have influenced its uptake [51]. In this context, faricimab presents a promising alternative for suboptimal responders owing to its dual Ang-2 and VEGF inhibition mechanism and favorable safety profile observed in clinical trials.

Looking at the proportion of dry retinas post IVF, 91% had retinal fluid prior to IVF, and nearly half of the patients (41%) achieved fluid resolution (regardless of whether it was IRF or SRF). One hypothesis about why the other half failed to achieve fluid resolution is that these patients have a long history of disease, they have been previously treated with other anti-VEGFs, which might have caused an evolution of the pathophysiology to encompass other pro-angiogenic factors driving fluid persistence [52]. Another possibility is that some intra- or sub-retinal fluid may not necessarily signify exudation from neovascularization but could rather be due to other effects on the macula, such as a breakdown of the RPE pump [53] or degeneration of retinal cells within the macula (i.e., cystoid degeneration).

Analyzing the outcomes of treatment-resistant patients, the change in BAVA and CST was statistically significant. These findings suggest that switching to IVF may have at least anatomic benefits both in patients considered to be “treatment resistant” as well as others that might have what was previously considered “anatomic stability” but with persistent fluid.

Reversion rate was reported in six studies, out of which four reported outcomes of treatment-resistant patients [25, 28, 32, 41], and these patients already were refractory to other anti-VEGFs, defined as persistence, recurrence, or worsening fluid after three or more anti-VEGF injections. The main reason for reversion was lack of sufficient effect reflected by worsening fluid or lack of improvement. In this difficult-to-treat population, a 23% rate of reversion back to prior therapy may therefore be expected if patients were already stable on their previous medication and no benefit of faricimab was observed. Complication rates of severe adverse events from our analysis (1.2%) are comparable to those from TENAYA and LUCERNE (1.2%) [9].

The limitations of this analysis include the variability in comparability of data due to interrupted time series and retrospective studies without randomization, mainly due to the nature of the topic that makes carrying out RCT challenging. Longer follow-up studies would be helpful to better understand the long-term outcomes of IVF. Heterogeneity was high in the included studies mainly due to differences in patient demographics, disease severity, and publication bias. The extension of injection intervals was not standardized between studies and maybe influenced by bias or need of the patient and/or the treating physician without necessarily achieving anatomic stability or improvement. Finally, some variables were reported in only a small number of studies, which might limit reproducibility and decrease the statistical power of the analysis.

Conclusions

This is the first study to our knowledge that meta-analyzed the visual and anatomical outcomes of IVF in previously treated patients with wAMD. This study demonstrated that BAVA improvement is modest and delayed until more than 6 months of treatment, CST improvement is rapid and sustained at 1 month and beyond, and injection interval may be extended (~2 weeks on average) and maintained after 6 months. Further studies stratifying patients on the basis of risk factors, disease history/severity, and race are needed to better understand the response of non-treatment naïve and treatment-resistant patients with wAMD to IVF.

Author Contributions

All authors contributed to the study conception and design; methodology—Ali Khodor, Manuel E. Quiroga-Garza, and Raul E. Ruiz-Lozano; formal analysis and investigation—Ali Khodor, Jonathan T. Caranfa, Tavish Nanda, Ali Chehab, and Eugenia M. Ramos-Dávila; writing—original draft preparation—Ali Khodor, Jonatha T. Caranfa, and Stephanie Choi; writing—review and editing—Jonathan T. Caranfa, Tavish Nanda, Stephanie Choi, Manuel E. Quiroga-Garza, Raul E. Ruiz-Lozano, Andre J. Witkin, Chirag P. Shah, and Jeffrey S. Heier; supervision—Andre J. Witkin.

Funding

No funding or sponsorship was received for the publication of this article.

Data Availability

The database and code used for this study are available upon request from the authors.

Declarations

Conflicts of interest

Chirag Shah is a consultant and clinical trialist for Genentech. Andre Witkin is a consultant and primary investigator for Genentech and Apellis and an Editorial Board member of Ophthalmology and Therapy. Andre Witkin was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Jeffrey Heier is a consultant for: 4DMT, Abbvie/Regenxbio, Abpro, Affamed, Alkeus, Annexon, Asclepix, Aviceda, Bayer, Beacon, Boehringer Ingleheim, Breye Therapeutics, Caeregen, Cogent, Complement Therapeutics, Curacle, Daiichi Sankyo, Emmetrope, Endogena, Frontera, Galimedix, Inflammx, Kaigene, Kanghong, Lilly, Manistee, Nanoscope, Notal Vision, Novartis, Ocuphire, OcuTerra, Opthea, Osanni, Ray Therapeutics, Regeneron, Samsung Bioepis, Sanofi, Skyline, Stealth, Laboratoires Thea, Unity Bio, Vanotech, and Visgenx; member of DSMC: Akouos; employee/executive: Chief Scientific Officer: Ocular Therapeutix; research investigator: 4DMT, Abbvie/Regenxbio, Annexon, Apellis, Astellas, Bayer, Beacon, Boehringer Ingleheim, Cognition Therapeutics, Curacle, Genentech/Roche, Janssen R&D, Kodiak, Notal Vision, Novartis, Oculis, Opthea, Perceive Bio, Regeneron, Sanofi, Skyline, Stealth Biotherapeutics, and Vanotech; holds equity in: Adverum, Aldeyra, Alzheon, Aviceda, Caeregen, Inflammx, jCyte, Manistee, Ocuphire, Ocular Therapeutix, Osanni Bio, Ray Therapeutics, RevOpsis, Vinci, Visgenx, and Vitranu. Ali Khodor, Jonathan T. Caranfa, Tavish Nanda, Raul E. Ruiz-Lozano, Manuel E. Quiroga-Garza, Stephanie Choi, Ali Chehab, and Eugenia M. Ramos-Dávila declare no conflicts of interest.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

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